OBJECTIVE: Our objective is to examine the genetic basis for the high risk of atherosclerosis and cardiovascular (CV) disease in rheumatoid arthritis (RA). Recent discoveries have implicated systemic inflammation in the pathogenesis of atherosclerosis. RA is characterized by both systemic inflammation, and a predisposition to atherosclerosis, raising the possibility that the two could be causally associated. However, the mechanism for such an association is not well understood. Early evidence implicating inflammation genes has been limited by the small number of genes studied. METHODS: We will examine the association between inflammation gene variants (i.e. single nucleotide polymorphisms, SNPs) and atherosclerosis, in patients with RA, and persons from the general population. We will seek SNPs associated with the atherosclerosis phenotype in key inflammation genes. We will define the phenotype using the carotid intima-media thickness (IMT) measured by ultrasound, and the incidence of CV events. We will test four hypotheses: That (1) Inflammation gene SNPs are associated with the atherosclerosis phenotype; (2) The presence of RA interacts with inflammation gene SNPs to modify their association with the atherosclerosis phenotype; (3) Inflammation gene SNPs modify the association between other factors related to CV risk, and the atherosclerosis phenotype; and (4) The association between inflammation gene SNPs and the atherosclerosis phenotype varies between ethnic groups. To test these hypotheses, we will study 1,000 members of SRALE (for Outcome of Rheumatoid Arthritis Longitudinal Evaluation), a cohort of RA patients, of whom 500 are Mexican American (MA) and 500 are non-Hispanic White; and 1,000 age-, sex- and ethnicity-matched participants in MESA (for Multi-Ethnic Study of Atherosclerosis), a study of atherosclerosis in the general population. The atherosclerosis phenotype has been ascertained in these two cohorts using equivalent definitions and techniques. Moreover, both cohorts include a considerable number of MAs, enabling ethnic matching. We will use high throughput techniques to seek an average of 20 carefully chosen and prioritized SNPs in each of 25 key inflammation genes. We will use Bayesian Quantitative Trait Nucleotide (BQTN) analysis, a novel statistical technique to efficiently evaluate the association between genetic variants and phenotypic traits, using Bayes factors. RELEVANCE: This research will advance considerably current knowledge about the role of inflammation genes in the atherosclerosis that occurs in RA. This new knowledge will be the basis for future efforts to reduce RA's high CV disease burden. For example, comprehensive characterization of atherosclerosis-associated SNPs could be used to enhance the accuracy of current CV risk stratification schemes. This would improve the prevention and early treatment of atherosclerosis in RA, improving survival. SNPs associated with atherosclerosis may also identify pathogenic mechanisms deserving of further attention as potential targets for novel interventions. People with inflammatory diseases such as rheumatoid arthritis (RA) have a high burden of atherosclerosis. We will examine the association between inflammation gene variants and atherosclerosis in RA patients and normal people of the same age and sex. Gene variants associated with atherosclerosis may identify pathogenic mechanisms that could be novel targets for intervention to reduce RA high cardiovascular (CV) morbidity and mortality, and could be used clinically to enhance current CV risk stratification strategies.